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- 赵军阳副主任医师
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医院:
首都医科大学附属北京儿童医院
科室:
眼科
- Primary chemotherapy prior to enucleation of eyes with retinoblastoma is associated reduced evidence of invasion on histopathology and increased risk of death from metastasis
- 作者:赵军阳|发布时间:2011-04-04|浏览量:453次
题目:Pre-enucleation Chemotherapy for Eyes Severely Affected by Retinoblastoma
Masks Risk of Tumor Extension and Increases Death from Metastasis
作者:Junyang Zhao, M.D.1, Helen Dimaras, Ph.D.4,5,11, Christine Massey, M.Sc.6,
Xiaolin Xu, M.D.2, Dongsheng Huang, M.D.3, Bin Li, M.D.2, Helen SL Chan, M.B., B.S.,北京同仁医院眼肿瘤科赵军阳
F.R.C.P.C., F.A.A.P.4,11, Brenda L. Gallie, M.D., F.R.C.S.C.5,7,8,9,10
作者单位:The Departments of 1Ophthalmology, 2Pathology and 3Oncology, Retinoblastoma
Group, Beijing Tongren Eye Centre, Beijing Tongren Hospital, Capital Medical
University, Beijing Ophthalmology & Visual Sciences Key Lab. 100730, Beijing, China;
The Departments of 4Hematology/Oncology and 5Ophthalmology and Visual Science,
The Hospital for Sick Children, 555 University Avenue, Toronto, ON Canada M5G 1X8;
The Departments of 6Biostatistics, and 7Medical Biophysics, University of Toronto, and
the Campbell Family Institute for Cancer Research, Ontario Cancer Institute/Princess
Margaret Hospital, University Health Network, 610 University Avenue, Toronto, ON,
Canada M5G 2M9; The Departments of 9Molecular Genetics, 10Ophthalmology,
11Pediatrics, University of Toronto, Medical Sciences Building, 1 King’s College Circle,
Toronto, ON, Canada M5S 1A8.
关键词:Keywords: Retinoblastoma; chemotherapy; metastasis; enucleation; pathology; TNM
staging.
摘要:ABSTRACT
背景:Background
Initial response of intraocular retinoblastoma to chemotherapy has encouraged primary
chemotherapy instead of primary enucleation for eyes with clinical features suggesting high risk
of extraocular extension or metastasis. Upfront enucleation of such high-risk eyes allows
pathologic evaluation of extraocular extension, key to management with appropriate
surveillance and adjuvant therapy. Does chemotherapy prior to enucleation mask histological
features of extraocular extension, potentially endangering the child’s life by subsequent undertreatment?
方法:Methods
We performed retrospective analysis of 100 eyes with advanced retinoblastoma enucleated with,
or without, primary chemotherapy, in Beijing Tongren Hospital, retrospectively from October
31, 2008. The extent of retinoblastoma invasion into optic nerve, uvea and anterior chamber on
histopathology was staged by pTNM classification. The treatment groups were compared for
pathological stage (Cochran-Armitage trend test) and disease-specific mortality (competing risks
methods).
结果:Results
Children who received chemotherapy prior to enucleation had lower pTNM stage than primarily
enucleated children (p=0.01). Five patients who received pre-enucleation chemotherapy died of
extension into brain or metastasis. No patients who had primary enucleation died. For children
with Group E eyes, disease-specific mortality (DSM) was higher with pre-enucleation
chemotherapy (n = 45) than primary enucleation (n = 37) (p=0.01). Enucleation more than 3
months after diagnosis was also associated with higher DSM (p<0.001).
结论:Conclusions
Chemotherapy prior to enucleation of E eyes with advanced retinoblastoma down-staged
pathological evidence of extraocular extension, and increased the risk of metastatic death from
reduced surveillance and inappropriate management of high risk disease, if enucleation was
performed more than 3 months after diagnosis.
介绍:INTRODUCTION
Metastasis of retinoblastoma is a rare event in the developed world, where most cases are
diagnosed early enough to achieve cure.1 Cure of retinoblastoma that has spread outside the eye
is rare. Therapy for metastatic retinoblastoma usually involves systemic and
intrathecal/intraventricular chemotherapy, stem cell transplant and in some cases radiation.2-8
Retinoblastoma that is confined to the eye can be cured by simple enucleation, and usually no
further treatment is necessary. The enucleated eye is studied for histopathological evidence of
tumor invasion or factors that would indicate risk of tumor spread outside the eye, and classified
by the American Joint Committee on Cancer (AJCC) pTNM Classification.9 Patients displaying
unfavorable risk factors on pathology may be treated with adjuvant chemotherapy, and/or active
surveillance to identify extraocular retinoblastoma when cure is still feasible.10
Intraocular retinoblastoma Groups A-D, International Intraocular Retinoblastoma
Classification (IIRC)11, can initially respond dramatically to chemotherapy. This has resulted in a
trend to also treat with chemotherapy more severely affected eyes in IIRC Group E, which
exhibit clinical signs associated with high risk for extraocular disease. This treatment may be due
in part to parental reluctance to remove the child’s eye, and in part to the expectation that
chemotherapy might make the surgical removal of the eye safer. However, chemotherapy might
down-stage pathological features associated with risk for extraocular extension, which should
otherwise require adjuvant therapy and/or surveillance. This could result in under-treatment and
loss of opportunity for cure.
We performed a retrospective case study of 100 enucleated IIRC Group D and E eyes that
were either primarily enucleated or treated with prior primary chemotherapy, in an attempt to
determine the effect of pre-enucleation chemotherapy on the histological detection of risk for
extraocular extension and patient outcome.
方法:METHODS
数据收集:DATA COLLECTION, ETHICS
All data were collected retrospectively with approval from the Capital Medical University,
Beijing Tongren Hospital Ethics Board. Data was analyzed with approval of the Research Ethics
Board of the University Health Network, Toronto, Canada. Anonymized clinical data were
recorded including gender, date of birth, age at diagnosis, disease laterality (unilateral/bilateral),
IIRC group at diagnosis, family history of retinoblastoma, follow-up duration and chemotherapy
regimen, evidence of extraocular extension and date of death.
INCLUSION AND EXCLUSION CRITERIA
Patients were selected based on the IIRC Group of their enucleated eye, confirmed at the
initial staging examination under anesthesia (EUA), and date of enucleation. All 100 IIRC
Group D or E eyes enucleated at the Beijing Tongren Hospital, Beijing, China, between May 19,
2006 and October 31, 2008, were included in this study. The eyes were enucleated either as
primary treatment or following chemotherapy.
No patient had clinical evidence of metastasis at presentation by lumbar puncture (LP), bone
marrow aspiration (BMA), and MRI and/or CT. For those who received chemotherapy, prechemotherapy
single freeze-thaw cryotherapy was used to increase drug penetration into the
eye.12 Children were excluded from this study if there was evidence of clinical metastasis at
presentation, or if they had been treated with chemotherapy plus focal laser and/or therapeutic
triple freeze-thaw cryotherapy, since this indicates more extensive effort to save the eye than
simple pre-enucleation chemotherapy.
病理评估:HISTOLOGICAL ASSESSMENT
The extent of tumor in optic nerve, choroid and anterior chamber were scored based on the
written histopathology reports and confirmed by retrospective re-review of hematoxylin & eosin
(H & E) stained slides. The AJCC pTNM stage9 was assigned to each eye based on histological
features including extent of tumor invasion into optic nerve, choroid, and/or anterior chamber.
Evidence of metastasis was collected from MRI, CT, LP and/or BMA reports. For some
analyses, children were grouped into low (pT1), moderate (pT2) or high (pT3, pT4) risk for
metastasis (Table 1).
数据分析:STATISTICAL ANALYSIS
Disease-specific mortality (DSM) was measured from date of diagnosis to date of death from
disease in the study eye. Death not due to disease from the study eye was treated as a competing
risk. Patients alive at last follow up were censored. Univariable analyses of disease-specific
survival were conducted using Gray’s test and plots of 1 minus the cumulative incidence
function. Other univariable analyses were conducted using Fisher’s exact test, the Wilcoxon
rank sum test, and the Cochran-Armitage trend test, and all p-values reported for these tests are
exact p-values. P-values reported for all tests are two-sided. There was no missing data.
Competing risks analyses13 were performed using the cmprsk package in R 2.10.1. All other
analysis was generated using SAS 9.2.
结果:RESULTS
PATIENTS
Histopathology reports of 100 enucleated retinoblastoma eyes from 100 children (61 male, 39
female; 28 bilateral, 72 unilateral; 18 Group D, 82 Group E) were retrospectively staged for
features required for pTNM staging. Re-examination of the histopathology by a second reviewer
(BLG) showed 100% concurrence with low, moderate and high-risk staging (Table 1).
Enucleation was the primary treatment for 45 eyes. Chemotherapy was the primary treatment
for 55 eyes, which were subsequently enucleated without other treatments. The two groups of
patients showed no significant differences between gender, unilateral vs bilateral, IIRC Group of
the worse eye, or age at diagnosis (Table 2). Median follow-up time was longer for patients alive
at last follow-up if they were treated with primary enucleation (median = 31.2 months; min/max
10.3 ? 44.9) than if they were treated with pre-enucleation chemotherapy (median = 25 months;
min/max 11.5-38.4) (Table 2).
Of the 28 patients with bilateral disease (Table 2, Fig. 2), only one (patient 33) had bilateral
Group E disease, diagnosed age 10 months. One eye was removed at diagnosis and was included
in this analysis. After enucleation, 5 cycles of chemotherapy were given, but the child was lost to
follow-up 19 months after diagnosis, so there is no further outcome for the retained Group E eye
or current status. The remaining patients had Groups A to D disease in the remaining eyes. Each
patient contributed only one eye to this study.
眼摘前的化疗:PRE-ENUCLEATION CHEMOTHERAPY
The pre-enucleation chemotherapy consisted of 1-12 cycles (median = 3 cycles) of CEV
(carboplatin-etoposide-vincristine)/CTV (carboplatin-teniposide-vincristine), with cyclosporine
doses lower than therapeutic doses previously published14, 15 for most children, administered
every 3-4 weeks. Approximately 24 to 48 hours before each chemotherapy cycle, examination
under anesthetic and pre-chemotherapy cryotherapy (single freeze-thaw to 1 or 2 spots in
peripheral retina) were performed to enhance chemotherapy penetration into the eye.12 Eyes
were removed when the tumors were judged to be progressing or active with no possibility of
useful vision.
TIME FROM DIAGNOSIS TO ENUCLEATION
Median time from diagnosis to enucleation was 0.1 months for primarily enucleated eyes, and 3
months for eyes that received pre-enucleation chemotherapy (p<0.001) (Table 2). Group E eyes
that received pre-enucleation chemotherapy were removed sooner (median = 2.8 months) than
Group D eyes (median = 8.6 months), indicating the poor response of Group E eyes to
therapeutic intervention (Table 2).
PRIMARY OUTCOMES
Five Children Died of Metastasis
No children who had primary enucleation (Figs. 1, 2), and no child with a Group D eye in the
study set, died of tumor. For E eyes, in the chemotherapy group, 4 (8.9%) of the children died
due to disease in the study eye by last follow up. Three were unilaterally and 1 was bilaterally
affected. One bilaterally affected patient (Patient 22) died from disease in the non-study eye,
which was considered a competing risk. For all of the children who died, the time from diagnosis
until enucleation was greater than 3 months. The remaining patients were censored. In the no
chemotherapy group none of the patients died due to disease by last follow up, 1 (2.7%) patient
experienced a competing risk (died not from tumor but from chemotherapy complications) and
the remaining 36 patients (97.3%) were censored at last follow up.
Patient 22 was diagnosed age 21 months with bilateral Groups E/D retinoblastoma, presenting
with leukocoria. The Group E eye was removed 2.5 months after completing 7 cycles of
chemotherapy. No adverse features were present on pathology (pT1), but 4 more cycles of
chemotherapy were given for the Group D eye. The optic nerve was found enlarged 1.5 years
after diagnosis, further treatment was refused, and the child died 2 years after diagnosis with
brain metastases from retinoblastoma.
Patient 38 was diagnosed age 24 months with bilateral Groups E/D retinoblastoma 9 months
after leukocoria was first noticed. After 8 cycles of chemotherapy, the Group E eye was
removed, 14 months after diagnosis. Pathology showed tumor at the cut end of optic nerve
(pT4b). Despite 6 more cycles of chemotherapy, the child died of brain metastasis, 2 years after
diagnosis.
Patient 68 was diagnosed age 35 months with unilateral Group E retinoblastoma, 2 weeks
after leukocoria was first noted. Despite 6 cycles of chemotherapy and external beam
radiotherapy, tumor was not controlled and the eye was removed, 10 months after diagnosis.
Pathology showed moderate risk with tumor past the lamina cribrosa but not to the cut end of
optic nerve (pT2a). The child was given 3 cycles of chemotherapy and 6 doses of intrathecal
chemotherapy as adjuvant therapy but died of brain and spinal metastases from retinoblastoma
2.5 years after diagnosis.
Patient 93 was diagnosed with unilateral Group E retinoblastoma at age 37 months. The eye
was removed after 4 cycles of chemotherapy. Pathology showed tumor at the cut end of optic
nerve and massive choroidal invasion (pT4b). Seven more cycles of chemotherapy were given
but the child died of brain metastasis 1.5 years after diagnosis.
Patient 94 was diagnosed age 9 months with unilateral Group E retinoblastoma, 2 months
after leukocoria was first noticed. Six cycles of chemotherapy were given, but recurrent
intraocular disease prompted enucleation 2 months later. Pathology showed no tumor past the
lamina cribrosa of the optic nerve but massive choroidal invasion and scleral invasion (pT4b).
Three more cycles of chemotherapy were given but the child died one year after diagnosis.
The children’s survival times were measured from their date of diagnosis. Because the time
intervals between diagnosis and enucleation were longer for the patients with pre-enucleation
chemotherapy (3.4 months versus 0.1 months for patients without pre-enucleation
chemotherapy), there is a design bias favoring the children who received pre-enucleation
chemotherapy with regards to their survival times. If pre-enucleation chemotherapy had no
effect on survival in any way whatsoever, the survival times for the patients with pre-enucleation
chemotherapy would tend to be longer than for those without pre-enucleation chemotherapy,
simply because they had to live through longer diagnosis-until-enucleation periods in order to be
included in the study. Despite this built-in bias, the disease-specific survival (DSS) was
significantly lower for children with Group E eyes who received chemotherapy prior to
enucleation than for those who did not (Fig. 1A; 24 month DSS was 95% and 100%,
respectively, Gray’s test p = 0.01), or if enucleation was delayed by more than 3 months (Fig.
1B; 24 month DSS was 90% and 100%, respectively, Gray’s test p <0.001). In the >3 months
group, 4 (16.7%) of the patients died due to disease by last follow up, and 1 patient died from
disease spread from the other eye (competing risk). The remaining patients were censored. In
the 0-3 month group, none of the patients died due to disease by last follow up, 1 (1.7%) patient
experienced a competing risk and the remaining 57 patients (98.3%) were censored at last follow
up. The median time until disease specific death cannot be estimated for the 0-3 months group
since there has not been enough follow up for their CIF to reach 0.50. The estimated median for
the >3 months group is 30.6 months.
Similarly, the number of cycles of chemo for all pre-enucleation chemo Group E patients,
significantly affected disease-specific death, comparing outcome for those who received >4
cycles to those who received ≤ 4 cycles (Gray’s test p = 0.01). The median time until disease
specific death in the >4 cycles group is 30.6 months.
The treatment groups were comparable by age at diagnosis and other demographic features.
The 1 bilateral child who died due to disease from the study eye was diagnosed at age 24
months, (median age for bilateral 15 months, range 4 to 77); the 3 children who died of unilateral
disease were diagnosed at ages 9, 35 and 37 months (overall unilateral age diagnosis median 27
months, range 4 to 77).
Histological Risk Factors Of Metastasis
Overall, pre-enucleation chemotherapy was associated with lower risk staging (p = 0.01) with
the pTNM stage collapsed into low, moderate and high-risk groups (Table 1). This was
significant for the D eyes (p = 0.02), and while the same trend held for the E eyes, the result was
not statistically significant (p = 0.09) (Table 3). Patient 68 died of intracranial extension of
unilateral retinoblastoma, yet the enucleated eye showed a risk level of pT2a, which would not
suggest the need for adjuvant treatment.
For the pre-enucleation chemotherapy patients, pTNM risk (low/moderate/high) was
negatively correlated with the amount of time between diagnosis and enucleation (Spearman
rank correlation coefficient = -0.30 (95% confidence interval (-0.47, -0.11), p = 0.002)).
POST-ENUCLEATION CHEMOTHERAPY
Seventy-four percent (74/100) of patients received chemotherapy (median 4 cycles, min = 1,
max =12) after enucleation (Fig. 2). The post-enucleation chemotherapy regimen was the same
as the pre-enucleation chemotherapy regimen described above. Overall, treatment with postenucleation
chemotherapy correlated to degree (low/moderate/high) of histological risk (p =
0.02), however, the number of cycles given was apparently not consistent for the pTNM the risk
groups. Fifty-two percent (13/25) of children with low-risk pathology and 81.3% (48/59) with
moderate-risk pathology received post-enucleation chemotherapy, although no published data
suggests that low and moderate-risk justifies adjuvant therapy.16 Nineteen per cent (3/16) of
children with high-risk pathology did not receive post-enucleation chemotherapy, which
conventionally would be clinically indicated.16 Univariable tests did not suggest that the decision
to give post-enucleation chemotherapy was associated with laterality or IIRC Group.
讨论:DISCUSSION
Next to India, China has the most new cases of retinoblastoma.1, 17 Accrual of such a large a
cohort of enucleated eyes in a short period of time (100 eyes in 2.5 years) is nearly impossible in
other countries, due to the low incidence of retinoblastoma.1, 17
We could not determine retrospectively the individual rationale for pre-enucleation
chemotherapy in each child. Based on anecdotal evidence, we speculated that the decisions
included a combination of desire to save the eye and vision, parental refusal of recommended
enucleation, and the misguided idea that treatment might make the eye ‘safer’ for eventual
enucleation. In actual fact, we show that pre-enucleation chemotherapy did not prevent tumor
dissemination, but actually masked unfavorable pathology that would warrant further therapy
and/or surveillance, since 5 children died from disease despite showing no evidence of tumor
dissemination at enucleation following pre-enucleation chemotherapy.
The AJCC pTNM staging is designed to assess the risk of tumor dissemination, and guide the
decision to provide further treatment and/or surveillance for the child. In the present patient
cohort, the post-enucleation chemotherapy regimen was not guided in a consistent fashion by the
risk indicated by pathological examination of the enucleated eyes (Fig. 3). For some bilateral
patients, the chemotherapy might have been given to treat the other eye, but several unilaterally
affected children who were primarily enucleated with no histopathological risk factors for
metastasis also received post-enucleation chemotherapy.
We speculate that if the 4 children who subsequently died of metastasis from their study eye
had undergone immediate enucleation, the cancer might have not yet extended outside the eye, or
if the high-risk pathological risk factors had not been masked at diagnosis, appropriate postenucleation
surveillance and adjuvant therapy might have avoided their metastatic deaths. The
low-dose cyclosporine and pre-enucleation chemotherapy given in this study was apparently
ineffective for treating tumors already outside the eye, or to prevent extension of tumor outside
the eye while the child was being treated with chemotherapy. Three of the 5 patients who died
showed high-risk pathology when the eyes were eventually enucleated, despite their preenucleation
chemotherapy. When significant high risk optic nerve invasion was recognized,
orbital radiotherapy in addition to the post-enucleation chemotherapy might have influence the
outcomes, but was not given.
Delay of treatment is known to contribute to poorer outcomes for children with
retinoblastoma, as did delay from “inadequate” treatment in an attempt to control Group D/E
disease, which might have masked the true extent of extraocular extension for the five children
who died. In addition, the pre-enucleation chemotherapy may have promoted multidrug
resistance, so that the post-enucleation chemotherapy was ineffective.
One patient died despite low-risk pathology (Patient 68, pT2a) in the enucleated eye,
suggesting that high-risk clinical and pathology features that led to death might have been
obscured by the pre-enucleation chemotherapy. We also observed pathological down-staging of
Group D eyes treated with pre-enucleation chemotherapy, suggesting chemotherapy could
indeed obscure staging.
Shorter follow-up times for children who received pre-enucleation chemotherapy indicated
that in general these patients were diagnosed more recently. This suggested an increasing clinical
practice trend to administer pre-enucleation chemotherapy. Our study suggests that this trend
carries a severe risk to the life of children with retinoblastoma. In comparison, the children with
unilateral Group E retinoblastoma who were primarily enucleated showed low or moderate
pathological risk factors for extraocular disease and none died.
The fewer Group D than E eyes enucleated in the study time period suggests that Group D
eyes are more often saved than E eyes, consistent with their less severe involvement. Several
published papers claiming cure of Group E eyes are mis-staged and actually Group D eyes.18, 19
Although a completely different study is required to assess the effectiveness of the chemotherapy
to save Group D eyes, in this treatment center, as far as can be determined, 99% of Group E eyes
were not saved by chemotherapy. If a Group E eye was not enucleated, it was because parents
refused treatment and did not return for follow-up, and these children likely died.
Though most children whose enucleation was delayed because of chemotherapy did not
develop metastasis, we have not ascertained what additional complications were caused by the
pre-enucleation chemotherapy. One child who had not received pre-enucleation chemotherapy,
died from post-enucleation chemotherapy toxicity. Formal studies are necessary to study the
impact of chemotherapy and repeated examinations under anesthesia on families and children.
Particularly, any immediate and future systemic side effects and risks and financial costs to
family and health resources must be weighed against the remote possibility of successful
treatment of severely involved eyes. Until proven otherwise, enucleation is the safer and better
option for all Group E eyes, most obviously in children with unilateral retinoblastoma when
there is a normal eye.
Our data reconfirmed the recommendation to primarily enucleate E eyes urgently.11, 20 In this
study, the delay of enucleation while chemotherapy was administered increased the opportunity
for retinoblastoma to invade and disseminate. The pre-enucleation also masked unfavorable
pathology that warranted further adjuvant therapy and/or surveillance. The longer interval
between time of noting the first sign of retinoblastoma, usually the bright white reflection at the
back of the eye known as leukocoria, to the time of treatment, adversely affects the outcome of
the child.21 Success to salvage Group D eyes ranges from 30-50% at retinoblastoma treatment
centers worldwide.22 Perhaps only when available treatment could cure more than 70% of Group
D eyes, and also cures early-detected extraocular retinoblastoma, should we attempt to save
Group E eyes. Such treatment done in the context of clinical trials will assure early detection of
unanticipated harms.
Unlike in other pediatric cancers, no significant clinical trials as yet support the care of
children with retinoblastoma.23 Starting in the 1950’s, radiation therapy for intraocular
retinoblastoma swept the world after dramatic responses in intraocular tumors.24 No clinical trial
evaluated the long-term outcomes of radiation. Only twenty years later was it shown that more
people had died of radiation-induced secondary cancers than of retinoblastoma.25 Chemotherapy
replaced primary radiation in the 1990’s,22 again with dramatic responses in intraocular
retinoblastoma, but again, no multicenter clinical trials have systematically evaluated negative
outcomes, such as the increased mortality we now document. Another “dramatic” therapy, intraarterial
chemotherapy, is presently being used widely for all stages of intraocular retinoblastoma,
including Group E eyes.26 The data we report here raise the alarming potential that children with
Group E tumors treated with intra-arterial chemotherapy face an increased risk of death from
metastasis, when simple enucleation of the eye would have saved their life with minimal
morbidity for unilaterally affected children.
Also alarming is the possibility that the remainder of the children on this study is not out of
danger, since with a longer follow-up more children may ultimately die of metastases.
ACKNOWLEDGEMENTS
We acknowledge the dedicated staff members of the Beijing Tongren Hospital Retinoblastoma
Centre, and Tony Panzarella, M.Sc., P.Stat., Michael Jewett, M.D., F.R.C.S.C. and Kirk
Vandezande, Ph.D., for their insight and helpful review of our manuscript. This research was
funded in part by the Ontario Ministry of Health and Long Term Care. The views expressed do
not necessarily reflect those of the OMOHLTC. We acknowledge the generous contributions of
the Kalmar Family Trust for the One Retinoblastoma World network. This research was funded
in part by the Canadian Retinoblastoma Society.
FIGURES
Figure 1. Disease-Specific Survival for children with enucleated Group E eyes.
Panel A shows disease-specific survival for children with Group E eyes who received
chemotherapy prior to enucleation (45) compared to those who did not (37).
Panel B shows disease-specific survival for children whose eyes were enucleated > 3
months (24) or ≤ 3 months (58) from diagnosis.
Figure 2. Cycles of pre-enucleation and post-enucleation chemotherapy.
Patients (identified by numbers) sorted by laterality (unilateral/bilateral), risk of
extraocular disease on pathology (L = low, white background; M= moderate, light
orange background; or H = high, dark orange background) and number of
chemotherapy cycles (blue bars, range from 0-12 cycles). Patients who died due to
disease are indicated in red outline with patient number in red and bold.
TABLES
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